Tyrosine kinases are an integral part of growth factor receptors and are essential for the propagation of growth factor signal transduction leading to cellular proliferation, differentiation, and migration. Growth factor receptors are also known as receptor tyrosine kinases (RTKs). The aberrant regulation of growth factors or their cognate receptors are reputed to play a critical role in the progression of proliferative diseases. Fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) have been implicated as important mediators of tumor promoted angiogenesis. Solid tumors are dependent upon the formation of new blood vessels from preexisting vessels (angiogenesis) to nourish their growth and to provide a conduit for metastases. Accordingly, inhibitors of the FGF and VEGF RTKs, as well as other tyrosine kinases, are useful agents for the prevention and treatment of proliferative diseases dependent on these enzymes.
WO 00/24744 (Harris et al.), WO 96/13262 (Thompson et al.), WO 01/64679 (Adams et al.), WO 01/29041 and WO 01/29042 (both to Dunn et al.) teach pyrimidopyrimidinone compounds useful in treating proliferative diseases.
Despite the progress that has been made, the search continues for small molecular weight compounds that are orally bioavailable and useful for treating a wide variety of human tumors and other proliferative disorders such as restenosis, angiogenesis, diabetic retinopathy, and atherosclerosis.